Abstract
Aim: Clonal haematopoiesis (CH) of indeterminate potential (CHIP) is defined as the detection of recurrent somatic mutations in genes known to drive haematological malignancies (such as DNMT3A, TET2, ASXL1) in individuals without haematological abnormalities. We hypothesised that the chronic inflammatory microenvironment in rheumatoid arthritis (RA) provides selective advantage to haematopoietic stem cells, engendering CH. We therefore evaluated the prevalence and pattern of CHIP in RA and its impact on disease activity (DA).
Method: DNA was extracted from the peripheral blood of 50 patients (aged 20–76 years old) with DMARD-naïve, seropositive early (<12 months) RA and analysed for CH using a custom-designed myeloid gene panel. Correlation between CH and disease parameters was performed.
Results: 16% (8/50) and 8% (4/50) RA patients harboured CHIP mutations with variant allele frequency (VAF) >0.5% and 2%, respectively. Patients >60 yo (n= 12) were more likely to have CHIP (58.3% vs 18.4%; p= 0.007) and VAF >2% (16.7% vs 5.3%; p= 0.2). Strikingly, prevalence was higher in the >60 yo group than the reported agematched frequency of 5.6%. Furthermore, 10% (5/50) of RA patients had ≥1 variants. The majority of 24 pathogenic variants (VAF >0.5%) involved DNMT3A (45.8%), TET2 (20.8%) and ASXL1 (12.5%). Importantly, mutations associated with high risk of progression to myeloid malignancy (TP53, SRSF2 and JAK2) were detected. Baseline high DAS28 was associated with higher frequency of CHIP mutations. Those with high baseline DA and CHIP mutations were less likely to respond to therapy: 66.7% (2/3) of this group were classified as nonresponders (DAS28 at 6 months) vs. only 17.4% (4/23) without CHIP mutation VAF >2% (p= 0.02).
Conclusion: Patients with RA have increased prevalence of CHIP, with implications on DA, response to therapy, and risk of further clonal expansion. Our findings warrant prospective studies to further characterise this subset of patients with RA.
Method: DNA was extracted from the peripheral blood of 50 patients (aged 20–76 years old) with DMARD-naïve, seropositive early (<12 months) RA and analysed for CH using a custom-designed myeloid gene panel. Correlation between CH and disease parameters was performed.
Results: 16% (8/50) and 8% (4/50) RA patients harboured CHIP mutations with variant allele frequency (VAF) >0.5% and 2%, respectively. Patients >60 yo (n= 12) were more likely to have CHIP (58.3% vs 18.4%; p= 0.007) and VAF >2% (16.7% vs 5.3%; p= 0.2). Strikingly, prevalence was higher in the >60 yo group than the reported agematched frequency of 5.6%. Furthermore, 10% (5/50) of RA patients had ≥1 variants. The majority of 24 pathogenic variants (VAF >0.5%) involved DNMT3A (45.8%), TET2 (20.8%) and ASXL1 (12.5%). Importantly, mutations associated with high risk of progression to myeloid malignancy (TP53, SRSF2 and JAK2) were detected. Baseline high DAS28 was associated with higher frequency of CHIP mutations. Those with high baseline DA and CHIP mutations were less likely to respond to therapy: 66.7% (2/3) of this group were classified as nonresponders (DAS28 at 6 months) vs. only 17.4% (4/23) without CHIP mutation VAF >2% (p= 0.02).
Conclusion: Patients with RA have increased prevalence of CHIP, with implications on DA, response to therapy, and risk of further clonal expansion. Our findings warrant prospective studies to further characterise this subset of patients with RA.
| Original language | English |
|---|---|
| Article number | e15171 |
| Number of pages | 1 |
| Journal | International Journal of Rheumatic Diseases |
| Volume | 27 |
| Issue number | Supplement 2 |
| DOIs | |
| Publication status | Published - Jun 2024 |
Keywords
- Clonal haematopoiesis
- rheumatoid arthritis
- chronic inflammatory microenvironments